Neither viral nor environmental factors explain the heterogeneous outcome of hepatitis C virus (HCV) infection. This and research on other chronic viral illnesses suggest host genomic polymorphisms are important. In the past, host-viral interaction has been difficult to investigate because of the complexity of both HCV pathogenesis and the human genome. However, the biology of HCV is unfolding and major technologic advances now make large-scale genotyping feasible. In this investigation, these new molecular tools are used to test the hypothesis that HCV pathogenesis, and in particular viral clearance and cirrhosis is influenced by the host genome. To accomplish this research, a DNA library will be constructed from subjects in four large HCV-infected cohorts, including 565 who have cleared viremia, 256 with cirrhosis, and more than one thousand with persistent viremia but no detectable cirrhosis. Polymorphisms in human leukocyte antigen alleles and putative pathogenic genes will be characterized and distortions in their frequency evaluated according to outcome. The molecular basis for observed associations will be further assessed coupling information on genetic linkage and HCV biology. Possible confounding factors (such as alcohol ingestion, HIV infection, or HCV genotype with cirrhosis) also will be examined using existing, detailed clinical databases. Success is anticipated at modest expense since experienced researchers will be using existing molecular tools to investigate large established cohorts.